Optimising Phase 1 oncology dosing schedule of an ATR inhibitor in real time using a model informed approach to predict myelosuppression
S. Y. Amy Cheung1, Alienor Berges1, James W. T. Yates1, Nuria Buil Bruna1, Graham Ross1, Simon Smith1, Brunella Felicetti1, Musaddiq Khan1, Christine Stephens1, Jean-Charles Soria2, Kevin Harrington3, Magnus Dillon3 and Simon J Hollingsworth1
1. AstraZeneca R & D, Cambridge, UK; 2. Institut Gustave Roussy, Paris, France; 3. Royal Marsden Hospital, London, UK
Introduction: AZD6738 is an ATR kinase inhibitor being tested in patients with solid malignancies as monotherapy and in combination. A quantitative understanding of duration and severity of myelosuppression is vital for dose-regimen optimisation in oncology [1]. As part of a model informed drug development [2], a PK-safety modelling approach was applied by integrating data across phase 1 studies to support dose-regimen selection.
Methods: The PK-safety model [3] was built in NONMEM, using emerging phase 1 PK, absolute platelet count (APC) and absolute neutrophil count (ANC) from 2 phase 1 studies of AZD6738 dosed alone (continuous doses from 40-480mg), or in combination intermittent doses from 80-320mg) with carboplatin and the PARP-1 inhibitor, olaparib. The model describes the baseline circulating count, a linear relationship between drug concentration and reduced proliferation in the bone marrow precursor cell population, a mean transit time (MTT) for the delay before reduction is seen in circulating cell counts and homeostasis increasing precursor proliferation to return cell counts to baseline. It was tested whether the effects of AZD6738, carboplatin and olaparib were additive or synergistic interactions. Simulations of the model in the software R were used to explore dose and schedule options.
Results: Blood counts in patients were well described by the model, following AZD6738 alone (n=32) and in combination with carboplatin AUC 5 every 3 weeks (n=33) and olaparib 300mg twice daily continuous dosing (n=31). AZD6738 was dosed on various intermittent regimen. AZD6738 alone showed a minimal impact on blood cell count compared to carboplatin and no synergy with carboplatin and olaparib could be estimated. The estimated mean MTT was 9 days in comparison to 5 days in the literature [3]. Simulations indicated that a 4 week treatment cycle of carboplatin and AZD6738 would provide time for APC and ANC to recover to 90% baseline. Continued reductions in cell counts are not predicted by the model whereas some patients with grade 2 reductions on cycle 1 experienced grade 4 on repeated cycles: Evaluation of alternative mathematical myelosuppression models [4] is ongoing.
Conclusion: The model simulations supported team decisions on dose and schedule and will minimise dose adjustments in future trials. Understanding single agent and combination safety profiles provided confidence for combination choices and differentiation strategy.
References:
[1] Berges et al Page 2017
[2] Marshall et al CPT: PSP 2017
[3] Friberg et al J Clin Oncol 2002
[4] Buil Bruna et al Page 2017
